Hepatoma derived growth factors (HDGF) have been cloned from man and mouse. When they bind to specific membrane receptors, they trigger intracellular signaling cascades. Some of these signaling events control the activities of transcription factors. The unregulated activity of transcription factors which govern cell proliferation may result in the growth and development of cancerous cells or in the release and differentiation of excess leukocytes.
Nakamura et al. (1994; J. Biol. Chem. 269:25143-49) described the human HDGF molecule as a monomeric, cytoplasmic peptide of 240 amino acids and approximately 25 kD which lacks a signal sequence and binds heparin. Northern analysis revealed that HDGF is expressed in several tumor derived cell lines and in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Based on its homology to high mobility group proteins (HMGs), location in the cytoplasm, and association with cellular proliferation in both normal and tumor cells, Nakamura et al (supra) predict that HDGF is a transcription factor which shows growth stimulating activity.
Baxevanis and Landsman (1995; Nucleic Acids Res 23:1604-13) aligned 121 HMG basic domains and reported that they fall into two groups, the HMG1/2 proteins with DNA binding ability and non-canonical HMGs, some of which are known to function as transcription factors. HMG1/2 proteins bind and alter the structure of DNA, making the molecule more amenable to the enzymes which carry out transcription. Support for this role comes from the fact that the half life of HMG1/2 proteins directly parallels the S phase of the cell cycle (Morton, R. L. et al. (1996) Biochem. Biophys Res Commun. 222:268-373). Other studies have shown that some HMGs possess a calmodulin binding domain (Harley, V. R. et al. (1996) FEBS Lett 391:24-28) and others associate with either hormone receptors as they bind DNA (Onate, S. A. et al. (1994) Mol Cell Biol 14:3376-91) or T-cell receptors as they regulate lymphocyte gene expression. These proteins enhance gene expression in the cells and tissues in which they are present.
HMGs have also been studied to determine their role in transforming fibroblasts and hematopoietic cells, in Burkitt's lymphoma (Morton, et al. supra), and in gastrointestinal carcinomas.
The discovery of polynucleotides encoding a lung growth factor variant, and the variant itself, provides a means to investigate cell proliferation under normal and disease conditions. Such cytokines or growth factor-like molecules related to hepatoma growth factor satisfy a need in the art by providing new diagnostic or therapeutic compositions useful in diagnosing and treating infections; autoimmune disorders, vascular diseases and cancers.